Glaucoma, which some estimate affects 2 million adults over 40, is an impairment of vision caused by too much fluid pressure within the eye.
Surgical treatment for glaucoma is effective; however, it is expensive and some surgeons will use surgery only as a last resort.
Carbonic anhydrase inhibitors, prescribed orally, work well to treat this disease, but they carry a host of side effects, for nausea to kidney stones.
Glaucoma stems from an excess of fluid behind the cornea, the three-layered tissue that acts as a window to let light enter. Fluid carrying nutrients such as potassium and glucose constantly wash the inside of the cornea to keep it healthy, much as tears wash the outside of the cornea.
In some middle-aged adults, fluids build up faster than can be absorbed back into the blood, for one of two reasons: the ciliary body (a tiny tissue behind the iris) may excrete too much fluid, or the fluid may not drain off at the normal rate.
Either way, the excess fluid damages the optic nerve. At first a glaucoma victim usually experiences a subtle loss of peripheral vision--objects will seem to disappear from certain spots to the side. But glaucoma often leads to middle-age blindness.
Unfortunately, the two approaches to general drug usage in treating glaucoma--topical (dropped into the eye) and oral--each have a peculiar set of side effects.
To make the long journey, oral drugs must be dosed in very high concentration. One class of drugs, called carbonic anhydrase inhibitors, slow the formation of fluid by inhibiting a chemical reaction at the ciliary body. Along with their well-tested effectiveness comes nausea, tingling in fingers and toes, and other side effects. Oral drugs generally do not, however, cause side effects in the eye.
Certain topical drugs, while causing less systemic effects, on the other hand, can cause severe headaches and constrict the pupil, making the daytime appear dark.
In our earliest parent application, analogs of 2-benzothiazole-sulfonamides are prepared as carbonic anhydrase inhibitors. While many of the compounds that are prepared are carbonic anhydrase active, in fact some have limited practical usage because the compounds do not penetrate the cornea very rapidly and/or may not distribute very well to the active site, i.e., ciliary body of the eye. This is not only true for certain carbonic anhydrase inhibitor active 2-benzothiazolesulfonamides, but it is also true for certain other carbonic anhydrase inhibitors such as methazolamide/acetazolamide analogs and dichlorphenamide analogs. In our application entitled PRODRUGS OF CARBONIC ANHYDRASE INHIBITORS, we prepared prodrugs of 2-benzothiazolesulfona-mides, methazolamide and dichlorphenamide analogs. This application is based upon the discovery that with regard to analogs of methazolamide particularly but also dichlorphenamide, the analogs themselves are active and will rapidly penetrate the cornea; therefore there is no need to go the extra step of preparing the prodrug.
Compounds which are carbonic anhydrase active inhibitors but have limited penetrability across the cornea and into the ciliary body are, as a practical matter, of limited value in developing topical carbonic anhydrase inhibitors even though they may inhibit the activity of carbonic anhydrase in vitro, i.e., in a test tube. Put another way, if the compound does not have the correct distribution and penetration properties, its chances of being pharmacologically active carbonic anhydrase inhibitor in patients are small, at best. Thus, it is important if one is developing effective carbonic anhydrase inhibitors which can be topically applied, that the compound not only be active in inhibiting carbonic anhydrase but also reach the active site.
It is a primary objective of the present invention to provide analogs of methazolamide and dichlorphenamide as carbonic anhydrase inhibitors with enhanced corneal penetration and ciliary body distribution properties without negatively impacting the carbonic anhydrase activity.
It is another objective of the present invention to prepare analogs of the above mentioned carbonic anhydrase inhibitors, in particular, methazolamide/acetazolamide and dichlorphenamide. The analogs have a high degree of corneal penetrability, and can effectively reach the inside of the eye and inhibit the pharmacologically active carbonic anhydrase inhibitor by enzymatic and/or hydrolytic degradation of a chemical bond between the drug moiety and carbonic anhydrase inhibitor.
An even further objective of the present invention is to prepare and use as topical carbonic anhydrase inhibitor compositions of novel analog compounds derived from methazolamide and dichlorphenamide.
The method and manner of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereinafter.